Investigating the quantitative toxicological relationship between PFAS alkyl fluorine structure and exposure levels leading to changes in blood-based clinical markers in rats

Perfluoroalkyl and polyfluoroalkyl substances (PFAS) are persistent organic pollutants, many of which exhibit low <i>in vivo</i> clearance rates. The long-chain PFAS (≥6 perfluorinated carbons), due to low clearance rates, are often perceived to exert a higher toll on human health than short-chain PFAS. However, a comprehensive toxicological and epidemiological comparison of long- and short-chain PFAS is overdue, leaving significant data gaps and limitations. For the first time, this study investigated the quantitative relationship between overall PFAS fluorine structure (C-F bond), which includes the alkyl chain length as one component, and PFAS doses that trigger changes in rat blood-based clinical markers. Fifteen markers published by the National Toxicology Program (NTP) after 28-day exposure to 7 PFAS with both long- and short-chain perfluorinated alkyl structures were examined. The aim of this study was to (1) determine PFAS doses that trigger changes in the marker levels for hepatic, renal, cardiovascular, and metabolic systems and (2) use these doses in multiple linear regression models to examine relationship to variables describing PFAS chemical structures. Our findings showed a log-linear dependence of alterations in marker levels on PFAS fluorine structure, as measured in the number of alkyl carbon-fluorine (C-F) bonds. Each C-F bond affected the marker effect levels by 0.45 ± 0.01 mmol/kg-day. The variety of studied clinical markers suggests that PFAS exposures led to deviations in multiple biological pathways in the rat animal model, which may inform future research and regulatory decisions. Perfluorinated carboxylic or sulfonic acids with linear chains of 4 to 10 carbons, known as perfluoroalkyl acids (PFAA)s, are types of PFAS commonly found in the environment.In a 28-day study by NTP, these PFAAs had dose-response effects in a panel of blood-based clinical markers in rats at specific doses.In regression models for individual clinical markers or a joint regression for all markers, these doses were strongly correlated with the number of carbon-fluorine bonds in the PFAAs.The resulting multiple linear regression (MLR) models provide a simple estimation tool for PFAAs’ exposure levels on blood-based clinical marker responses in rats. Perfluorinated carboxylic or sulfonic acids with linear chains of 4 to 10 carbons, known as perfluoroalkyl acids (PFAA)s, are types of PFAS commonly found in the environment. In a 28-day study by NTP, these PFAAs had dose-response effects in a panel of blood-based clinical markers in rats at specific doses. In regression models for individual clinical markers or a joint regression for all markers, these doses were strongly correlated with the number of carbon-fluorine bonds in the PFAAs. The resulting multiple linear regression (MLR) models provide a simple estimation tool for PFAAs’ exposure levels on blood-based clinical marker responses in rats.